• 1.

    Baber U, et al. Coronary plaque composition, morphology, and outcomes in patients with and without chronic kidney disease presenting with acute coronary syndromes. JACC Cardiovasc Imaging 2012; 5:S53S61.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Fang Y, et al. Early chronic kidney disease–mineral bone disorder stimulates vascular calcification. Kidney Int 2014; 85:142150.

  • 3.

    Li X, Giachelli CM. Sodium-dependent phosphate cotransporters and vascular calcification. Curr Opin Nephrol Hypertens 2007; 16:325328.

  • 4.

    Giachelli CM. The emerging role of phosphate in vascular calcification. Kidney Int 2009; 75:890897.

  • 5.

    Schafer C, et al. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 2003; 112:357366.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Suliman ME, et al. Vascular calcification inhibitors in relation to cardiovascular disease with special emphasis on fetuin-A in chronic kidney disease. Adv Clin Chem 2008; 46:217262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Cranenburg EC, et al. Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. Thromb Haemost 2009; 101:359366.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Schurgers LJ, et al. The circulating inactive form of matrix Gla protein is a surrogate marker for vascular calcification in chronic kidney disease: A preliminary report. Clin J Am Soc Nephrol 2010; 5:568575.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Schlieper G, et al. Circulating nonphosphorylated carboxylated matrix Gla protein predicts survival in ESKD. J Am Soc Nephrol 2011; 22:387395.

  • 10.

    Fusaro M, et al. Vitamin K, vertebral fractures, vascular calcifications, and mortality: Vitamin K Italian (VIKI) dialysis study. J Bone Miner Res 2012; 27:22712278.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Delanaye P, et al. Dephosphorylated-uncarboxylated matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrol 2014; 15:145.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Meuwese CL, et al. Associations between thyroid hormones, calcification inhibitor levels and vascular calcification in end-stage renal disease. PLoS One 2015; 10:e0132353.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Thamratnopkoon S, et al. Correlations of plasma desphosphorylated uncarboxylated matrix Gla protein with vascular calcification and vascular stiffness in chronic kidney disease. Nephron 2017; 135:167172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Westenfeld R, et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: A randomized trial. Am J Kidney Dis 2012; 59:186195.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Caluwe R, et al. Vitamin K2 supplementation in haemodialysis patients: A randomized dose-finding study. Nephrol Dial Transplant 2014; 29:13851390.

Vitamin K and Vascular Calcification

  • 1 Pascale Khairallah, MD, is a nephrology fellow at Columbia University Medical Center.
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Pascale Khairallah

Citation: Kidney News 11, 12

Despite many advances in the care of patients with chronic kidney disease (CKD) and ESKD, cardiovascular (CV) disease remains the leading cause of death in the kidney disease patient population. One of the factors explaining this excess mortality risk is vascular calcification, which predisposes patients to myocardial ischemia, left ventricular hypertrophy, and stroke (1).

The pathophysiology of vascular calcification in patients with CKD and ESKD is distinct from that in the general population. In the general population, vascular calcifications form in the intima of vessels and are linked to traditionally modifiable risk factors, including smoking, age, obesity, diabetes, hypertension, and hypercholesterolemia. By contrast, in CKD and ESKD, vascular calcifications form in the intima and media of medium and large arteries. Whereas the pathogenesis of intimal vascular calcification in CKD and ESKD mirrors that of the general population, the pathogenesis of medial vascular calcification is not well understood.

Medial vascular calcification occurs early in the course of CKD (2) and strongly predicts cardiovascular (CV) events and mortality. Mineral–bone disorder is a major factor involved in the development of medial vascular calcification (3, 4). Other involved factors include vascular smooth muscle cell osteochondrogenic shift (4), decreased levels of calcification inhibitors (5, 6), and increased levels of oxidative stress, all of which contribute to the progression of vascular calcification. Medial vascular calcification is a highly regulated multipathway process (4), but there are not yet any proven preventative treatments. Vitamin K supplementation is one potential therapy that is currently being investigated in clinical trials.

The role of vitamin K in vascular calcification

Matrix Gla protein (MGP) plays an important role in vascular biology. It is present in soft tissue, where it functions as a calcification inhibitor. MGP requires vitamin K to undergo γ carboxylation, an important step for MGP activity. In states of vitamin K deficiency, MGP remains decarboxylated and inactive, therefore increasing soft tissue propensity for calcification (Figure 1). Calcified vessels have higher concentrations of the dephosphorylated uncarboxylated form of MGP (dp-ucMGP), whereas normal vessels have higher concentrations of the carboxylated form of MGP (cMGP).

Figure 1.
Figure 1.

Hepatic and peripheral carboxylation of vitamin K–dependent proteins

Citation: Kidney News 11, 12

Vitamin K–dependent proteins undergo carboxylation to become biologically active, requiring vitamin K as a cofactor in the conversion. Abbreviation: MGP = matrix Gla protein. Adapted from Danziger J. Vitamin K–dependent proteins, warfarin, and vascular calcification. Clin J Am Soc Nephrol 2008; 3:1504–1510.

Vitamin K in CKD and ESKD

Patients with CKD and ESKD have vitamin K deficiency, which stems from multifactorial causes. The Western diet does not provide enough vitamin K to activate MGP in all tissues. The poor oral intake and the dietary restrictions of patients with advanced CKD and ESKD further contribute to vitamin K deficiency. Additionally, it is suggested that some phosphate binders can sequester vitamin K in the gut, therefore compounding the deficiency. Finally, the use of vitamin K antagonists such as warfarin inhibits vitamin K–dependent carboxylation of MGP. These agents have historically been associated with the progression of vascular calcification in patients with kidney disease.

With the discovery of the role of MGP in vascular calcification, vitamin K was proposed as a treatment to modify the development of vascular calcification and the risk of CV disease in CKD. Circulating MGP is used as a surrogate of vitamin K status: dp-ucMGP level inversely correlates with vitamin K level. Multiple observational studies have shown significant associations between higher levels of dp-ucMGP and lower levels of cMGP with vascular calcification in patients with CKD and ESKD (Table 1). These studies were cross-sectional; therefore, causal inferences could not be made. Subsequent studies evaluated the effect of vitamin K supplementation on vascular calcification. In patients with ESKD, supplementation with vitamin K resulted in a decrease of dp-ucMGP levels (Table 2). However, we cannot make any conclusions with certainty based on these studies because they were limited to 6 to 8 weeks of follow-up and did not measure vascular calcification scores. Clinical trials evaluating the effect of long-term vitamin K supplementation on vascular calcification, cardiovascular events, and mortality are currently ongoing.

Table 1.

Association between vitamin K level and vascular calcification in CKD and ESKD

Table 1.
Table 2.

Effect of vitamin K supplementation on dephosphorylated-uncarboxylated MGP level in ESKD

Table 2.

What can we do now?

While we await the ongoing vitamin K supplementation clinical trials that will give us a more definite answer to the question whether vitamin K supplementation can improve CV outcomes in patients with kidney disease, should we be giving all our CKD and ESKD patients vitamin K supplements?

There is no known toxicity of vitamin K, nor is there an upper level of intake. Additionally, vitamin K supplementation does not seem to increase the risk of thrombosis or stroke. Therefore, it seems to be a treatment with relatively little harm but with potentially significant benefit—a treatment that we may be justified to use more liberally.

Furthermore, should we be actively switching our patients from vitamin K antagonists such as warfarin to the novel anticoagulants when possible? This is currently recommended in patients with calciphylaxis, but we should perhaps be more liberal in prescribing novel anticoagulant agents for our patients with CKD and ESKD. This effort may decrease CV events and improve outcomes in these patients.

In conclusion, vitamin K is one piece of the puzzle of vascular calcification—a process that is unlikely to be reversed by targeting one pathway only. Targeting several pathways, including vitamin K deficiency, mineral–bone disorders, and the bone–vascular axis could improve vascular calcification development and progression. Further research into the mechanisms of vascular disease in CKD will ultimately lead to the development of therapeutic agents that can improve the risk of CV disease in kidney disease.

References

  • 1.

    Baber U, et al. Coronary plaque composition, morphology, and outcomes in patients with and without chronic kidney disease presenting with acute coronary syndromes. JACC Cardiovasc Imaging 2012; 5:S53S61.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Fang Y, et al. Early chronic kidney disease–mineral bone disorder stimulates vascular calcification. Kidney Int 2014; 85:142150.

  • 3.

    Li X, Giachelli CM. Sodium-dependent phosphate cotransporters and vascular calcification. Curr Opin Nephrol Hypertens 2007; 16:325328.

  • 4.

    Giachelli CM. The emerging role of phosphate in vascular calcification. Kidney Int 2009; 75:890897.

  • 5.

    Schafer C, et al. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 2003; 112:357366.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Suliman ME, et al. Vascular calcification inhibitors in relation to cardiovascular disease with special emphasis on fetuin-A in chronic kidney disease. Adv Clin Chem 2008; 46:217262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Cranenburg EC, et al. Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. Thromb Haemost 2009; 101:359366.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Schurgers LJ, et al. The circulating inactive form of matrix Gla protein is a surrogate marker for vascular calcification in chronic kidney disease: A preliminary report. Clin J Am Soc Nephrol 2010; 5:568575.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Schlieper G, et al. Circulating nonphosphorylated carboxylated matrix Gla protein predicts survival in ESKD. J Am Soc Nephrol 2011; 22:387395.

  • 10.

    Fusaro M, et al. Vitamin K, vertebral fractures, vascular calcifications, and mortality: Vitamin K Italian (VIKI) dialysis study. J Bone Miner Res 2012; 27:22712278.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Delanaye P, et al. Dephosphorylated-uncarboxylated matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrol 2014; 15:145.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Meuwese CL, et al. Associations between thyroid hormones, calcification inhibitor levels and vascular calcification in end-stage renal disease. PLoS One 2015; 10:e0132353.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Thamratnopkoon S, et al. Correlations of plasma desphosphorylated uncarboxylated matrix Gla protein with vascular calcification and vascular stiffness in chronic kidney disease. Nephron 2017; 135:167172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Westenfeld R, et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: A randomized trial. Am J Kidney Dis 2012; 59:186195.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Caluwe R, et al. Vitamin K2 supplementation in haemodialysis patients: A randomized dose-finding study. Nephrol Dial Transplant 2014; 29:13851390.

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